1. Field of the Invention
The present invention is concerned with providing a novel polypeptide which is a human TNF N-terminal mutein and relates to the polypeptide itself, a pharmaceutical composition containing the polypeptide, a process for producing the polypeptide, a recombinant DNA sequence encoding the polypeptide, a plasmid containing the recombinant DNA sequence and a transformed microbial cell having the plasmid.
2. Discussion of Background
TNF (tumor necrosis factor alpha) is a physiologically active compound, which was found to be present in the serum of a mouse preliminarily transfected with Bacillus Calmette Guerin (BCG) and treated by endotoxin, by Carswell et al. in 1975 (Proc. Natl. Acad. Sci. USA, 72, 3666 (1975)). In 1984, cDNA of human TNF was cloned by Pennica et al., and the entire primary structure (amino acid sequence) of the human TNF protein was clarified (Nature, 312, 724 (1984)). TNF has specific antitumor effects such as a cytotoxic activity against tumor cells and hemorrhagia necrosis or growth inhibition against transplanted tumors. However, it has been reported recently that side effects such as hyperlipemia, hypotension or fever, are likely to result from the administration of TNF. Accordingly, many research and development effects are being made to obtain a product superior in the activity as compared to TNF, while exhibiting reduced side effects. For example, Japanese Unexamined Patent Publications No. 40221/1986 (U.S. Pat. No. 4,650,674), No. 119692/1988 (U.S. Pat. No. 4,990,455) and No. 277488/1989 (EP-A-340,333) disclose deletion of a certain specific amino acid residues in the human TNF protein, or replacement of such an amino acid residues by other amino acid residues or addition of other amino acid residues, to provide a human TNF mutein.
However, it has not yet been possible to obtain a human TNF mutein having fully satisfactory pharmacological effects.